CD8+ T cell metabolism in infection and cancer

Abstract

Cytotoxic CD8⁺ T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8⁺ T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8⁺ T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8⁺ T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8⁺ T cell-mediated immunity. Defining the metabolic adaptations of CD8⁺ T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8⁺ T cell programmes and discuss how metabolism is integrated with CD8⁺ T cell differentiation and function and determined by environmental cues.

Fig. 1 |. Organismal, niche and intrinsic metabolism dictate CD8⁺ T cell fate and function.

Effector CD8⁺ T cells spearhead the adaptive branch of the immune system by directly killing infected cells and cancer cells, while long-lived memory CD8⁺ T cell populations provide protective immunity for the lifetime of the organism. In the setting of chronic viral infection and cancer, the tissue environment helps drive CD8⁺ T cells to a dysfunctional state known as T cell exhaustion. These functions of T cells are intimately linked to their capacity to obtain nutrients from heterogenous tissue environments (microenvironment), which are in turn influenced by tissue-specific activities and the overall organismal metabolism (the macroenvironment) to further influence the fate of CD8⁺ T cells. TF, transcription factor.

Fig. 2 |. Metabolism of CD8⁺ T cell activation and effector function.

a | CD8⁺ T cell activation increases metabolic activity — including nutrient uptake (red circles) and secretion of metabolic by-products (purple circles) — to fuel increased anabolism and proliferation needed to mount effector T cell responses and differentiation into long-lived memory CD8⁺ T cells. b | Immediately after CD8⁺ T cell activation, glucose-derived carbons are diverted from the TCA cycle into lactate production, a less efficient but faster route of ATP production, without increasing the overall glucose uptake. This is achieved in a CD28-independent fashion by engaging the pyruvate dehydrogenase kinase 1 (PDHK1)-dependent inhibition of pyruvate dehydrogenase (PDH) at the T cell synapse. Shortly after, glucose uptake is boosted by increasing the amount of glucose transporters on the cell surface, and the overall flux through glycolysis is upregulated by PI3K–AKT-dependent signalling downstream of CD28. Kinases are coloured green, metabolic enzymes are coloured blue, transporters are coloured pink and transcription factors are coloured light pink. c | CD8⁺ T cell activation requires increased nutrient consumption from the environment to support differentiation of T cells into effector and memory subsets. αKG, α-ketoglutarate; APC, antigen-presenting cell; ETC, electron transport chain; FADH₂, dihydroflavin adenine dinucleotide; LAT, linker for activation of T cells family member 1; LDH, lactate dehydrogenase; MPC, mitchondrial pyruvate carrier; mTORC1, mechanistic target of rapamycin complex 1; NFAT1, nuclear factor of activated T cells 1; PGC1α, peroxisome proliferator-activated receptor-γ coactivator 1α; PI3K, phosphoinositide 3-kinase; SAM, S-adenosylmethionine; SLC, solute carrier; TCA, tricarboxylic acid; TCR, T cell receptor.

Fig. 3 |. Metabolism of memory CD8⁺ T cell differentiation.

a | CD8⁺ T cell subsets along their differentiation trajectory can be segregated on the basis of their extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), which are a proxy for glycolytic and oxidative phosphorylation (OXPHOS) metabolism, respectively, as measured by Agilent Seahorse XF analysers (TABLE 1). b | Intrinsic metabolism of memory CD8⁺ T cells. Glucose-derived carbons are oxidized mostly through OXPHOS in the mitochondria. Fatty acid (FA)-binding proteins (FABPs) coordinate the uptake and intracellular management of lipids, either from extracellular uptake or from synthesis from glucose-derived carbons. Lipids are oxidized in the mitochondria through FA oxidation (FAO) via a mitochondrial transport mechanism involving the carnitine shuttle. The pentose phosphate pathway (PPP) provides the necessary NADPH to maintain adequate redox levels, fuel FA synthesis and provide metabolic intermediates for the synthesis of nucleotides. Growth factors and the overall metabolic and energetic state of the cell control mechanistic target of rapamycin complex 1 (mTORC1)–mTORC2 complexes to coordinate the flux of nutrients into anabolic or catabolic processes. Kinases are coloured green, metabolic enzymes are coloured blue, transporters are coloured pink, transcription factors are coloured light pink and other proteins are coloured orange. AMPKα, 5’-AMP-activated protein kinase catalytic subunit-α; AQP9, aquaporin 9; CPT1α, carnitine palmitoyltransferase 1α; DRP1, dynamin-related protein 1; ETC, electron transport chain; MCJ, methylation-controlled J protein; 6-P, 6-phosphate; PDH, pyruvate dehydrogenase; PI3K, phosphoinositide 3-kinase; TAG, triacylglycerol; TCA, tricarboxylic acid; TSC, tuberious sclerosis complex.

Fig. 4 |. Metabolism of tissue-resident memory CD8⁺ T cells.

a | Environmental sensing and survival in peripheral tissues. Tissue-resident memory CD8⁺ T cells sense concentrations of extracellular ATP (eATP) through P2RX7 to engage signalling that impacts survival. Expression of BHLHE40, which is restricted to tissue-resident memory CD8⁺ T cells, increases survival and mitochondrial metabolism to favour tissue residency. Expression of surface proteins, such as CD103 and CD69, favours tissue retention by blocking tissue egress signals, such as the sphingosine 1-phosphate (S1P) gradient established between the circulation and peripheral tissues. Transcription factors are coloured light pink and other proteins are coloured orange. b | Tissue-resident memory CD8⁺ T cells at barrier surfaces, such as skin and gut, use glucose and lipids to fuel the production of mitochondrial ATP. Fatty acid (FA)-binding protein (FABP) isoform expression is tissue specific and adapted to environmental lipid species. The cardiolipin composition of the mitochondria, controlled by the protein tafazzin, is a key aspect of their functionality. Transporters are coloured pink c | Tissue-resident memory CD8⁺ T cells at non-barrier surfaces, such as liver and fat, use glucose and lipids to fuel the production of mitochondrial ATP. FABP isoform expression is tissue specific and adapted to environmental lipid species. Autophagy promotes intracellular detoxification of damaged organelles, recycles nutrients and ensures mitochondrial homeostasis. Metabolic enzymes are coloured blue, transporters are coloured pink, transcription factors are coloured light pink and other proteins are coloured orange. AA, amino acid; FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; S1PR1, sphingosine-1-phosphate receptor 1.

Fig. 5 |. Metabolic insufficiency in chronic infection and cancer.

a | Metabolic insufficiency by nutrient competition and intercellular exchanges in the tumour microenvironment (TME). CD8⁺ T cells compete for nutrients with other cells in the TME, predominantly with cancer cells, which can deplete glucose and glutamine pools, and release immunosuppressive metabolites and ions, such as lactate, kynurenine and potassium ions. Additional immune cells, such as myeloid-derived suppressor cells, tumour-associated macrophages and regulatory T cells also contribute to the generation and secretion of metabolites that suppress CD8⁺ T cells. Chronic antigen presentation and low oxygen concentrations promote CD8⁺ T cell dysfunction by driving AKT-mediated and BLIMP1-mediated suppression of PGC1α, causing mitochondrial production of reactive oxygen species (ROS). Mitochondrial-derived ROS promote NFAT-driven exhaustion programmes. In addition to signalling through P2RX7, extracellular ATP can be subsequently converted to AMP and adenosine by the actions of CD39 and CD73, respectively. Adenosine signalling through adenosine receptor A_2A (A2AR) drives expression of PD1 on CD8⁺ T cells. PD1 signalling triggered by its ligand PDL1 on the surface of surrounding cells inhibits further CD8⁺ T cell activation, acting in part through its suppressive effect on mitochondrial metabolism. Secretion of arginase by tumour-associated macrophages and other cells depletes arginine pools from the TME and limits the antitumour effect of CD8⁺ T cells. Kinases are coloured green, metabolic enzymes are coloured blue, transporters are coloured pink, transcription factors are coloured light pink and other proteins are coloured orange. b | Metabolic insufficiency and exhaustion programmes. Upon infiltration into the tumour microenvironment, CD8⁺ T cells increase their metabolism to increase proliferation and cytotoxicity. However, prolonged exposure to persistent antigen and an immunosuppressive microenvironment drives them to dysfunction, a spectrum of differentiation states also known as exhaustion. A combination of metabolic imbalances and opposing cues (that is, chronic stimulation and pro-proliferation cues combined with lack of functional mitochondria and nutrients and diminished glucose uptake or lipid accumulation) pushes them further into a late non-reversible exhaustion state that is associated with failed antitumour immune responses. Manipulation of CD8⁺ T cell metabolism through genetic, pharmacological and metabolic interventions can oppose immunosuppressive factors and prevent differentiation to a dysfunctional state. AHR, aryl hydrocarbon receptor; AKTi, AKT inhibitor; BH4, tetrahydrobiopterin; DRP1, dynamin-related protein 1; GPX1, glutathione peroxidase 1; HIF1α, hypoxia inducible factor 1α; KO, knockout; NFAT, nuclear factor of activated T cells; OXPHOS, oxidative phosphorylation; PGC1α, peroxisome proliferator activated receptor gamma coactivator 1α; PPAR, peroxisome proliferator-activated receptor; SRC, spare respiratory capacity; TCR, T cell receptor; VHL, von Hippel–Lindau disease tumour suppressor.